1. Field of the Invention
The invention is in the field of organic chemistry. The invention relates to a process for the synthesis of (3R)-3-hydroxy-β-ionone and (3S)-3-hydroxy-β-ionone in high enantiomeric purity from commercially available (rac)-α-ionone. These ionones have been transformed into (3R,3′R)-zeaxanthin, (3S,3′S)-zeaxanthin, (3R,3′S;meso)-zeaxanthin, (3R)-β-cryptoxanthin, and (3S)-β-cryptoxanthin by a C15+C10+C15 coupling strategy according to known procedures.
2. Background Art
(3R)-3-Hydroxy-β-ionone and (3S)-3-hydroxy-β-ionone are two important intermediates in the synthesis of carotenoids with β-end group such as lutein, zeaxanthin, β-cryptoxanthin, and their stereoisomers. However, among the various stereoisomers of these carotenoids, only (3R,3′R,6′R)-lutein, (3R,3′R)-zeaxanthin, and (3R)-β-cryptoxanthin are present in most fruits and vegetables commonly consumed in the US. These carotenoids accumulate in the human plasma and major organs and exhibit antioxidant and anti-inflammatory properties that are important biological functions in protection against chronic diseases. (3R,3′R,6′R)-Lutein and (3R,3′R)-zeaxanthin also accumulate in the human ocular tissues [macula, retinal pigment epithelium (RPE), ciliary body, iris, lens] and have been implicated in the prevention of age-related macular degeneration (AMD). (3R)-β-Cryptoxanthin is also present in selected ocular tissues at a very low concentration whereas (3R,3′S;meso)-zeaxanthin which is absent in foods and human plasma is present in nearly all tissues of the human eye in relatively high levels. The biological activity of the other non-dietary stereoisomers of these carotenoids is not known at present. The structures of all possible stereoisomers of zeaxanthin (1-3) and β-cryptoxanthin (4 and 5) are shown in Scheme 1.
The first total synthesis of optically inactive (rac)-zeaxanthin and (rac)-β-cryptoxanthin was first reported in 1957 by Isler et al. (Helv. Chim. Acta, 1957, 40:456-467) employing C19+C2+C19 and C19+C21 Wittig coupling strategies, respectively. However, a more practical total synthesis of these carotenoids was developed by Loeber et al. [J. Chem. Soc (C), 1971, 404-408] by implementing a C15+C10+C15 double Wittig reaction for synthesis of (rac)-zeaxanthin and a C25+C15 Wittig coupling reaction for the synthesis of (rac)-β-cryptoxanthin as shown in Scheme 2.
According to this procedure, the key intermediates for the synthesis of (rac)-zeaxanthin was (rac)-3-hydroxy-(β-ionylideneethyl)triphenylphosphonium bromide that was coupled with the commercially available C10-dialdehyde 6 in a double Wittig reaction to yield a racemic mixture of 1-3 (Scheme 2). Similarly, (rac)-β-cryptoxanthin (4+5) was prepared by the Wittig condensation of the readily accessible β-apo-12′-carotenal (7) with (rac)-3-hydroxy-(β-ionylideneethyl)triphenylphosphonium bromide (C15-Wittig salt). This C15-Wittig salt was prepared in 8 steps from 4-ethylenedioxy-2,2,6-trimethylcyclohexanone that was sequentially converted to (rac)-3-hydroxy-β-ionone [mixture of (3R): 8 and (3S): 9] and 3-hydroxy-vinyl-α-ionol [mixture of (3R): 10 and (3S): 11] (Scheme 3).
The first total synthesis of optically active (3R)-3-hydroxy-(β-ionylideneethyl)-triphenylphosphonium chloride (12) and its (3S)-isomer (13) was reported in 1980 by Rüttimann and Mayer (Helv. Chim. Acta, 1980, 63:1456-62) according to Scheme 4. The key starting materials in this synthesis were (3R)-3-hydroxy-β-cyclogeranial and (3S)-3-hydroxy-β-cyclogeranial that were each prepared in 5 steps from 2,6,6-trimethyl-1,3-cyclohexadiene-1-carboxaldehyde (Safranal). These aldehydes were then converted to (3R)-3-hydroxy-β-ionone (8) and (3S)-3-hydroxy-β-ionone (9). In the following steps, the method of Loeber et al. [J. Chem. Soc (C), 1971, 404-408] was employed to transform these hydroxyionones into (3R)-3-hydroxy-(β-ionylideneethyl)triphenylphosphonium chloride (12) and its (3S)-isomer (13). However, the major difference was that the optically active (3R)-3-Hydroxy-β-ionone (8) and (3S)-3-hydroxy-β-ionone (9) were separately converted to (3R)-3-hydroxy-vinyl-α-ionols (10) and its (3S)-isomer (11), respectively. The optically active Wittig salts 12 and 13, prepared from these ionol, were then transformed into (3R,3′R)-, (3S,3′S)-, and (3R,3′S;meso)-zeaxanthin in double Wittig reactions with C10-dialdehyde 6 similar to the method of Loeber et al. shown in Scheme 2.
Two additional processes for the technical synthesis of (3R,3′R)-zeaxanthin via Wittig salt 12 were also developed a decade later by Widmer et al. (Helv. Chim. Acta, 1990, 73:861-67) and Soukup et al. (Helv. Chim. Acta, 1990, 73:868-873). These processes did not involve 3-hydroxy-β-ionone as an intermediate and in both cases employed 4-hydroxy-2,2,6-trimethylcyclohexanone as the key starting material.
In summary, since 1971 numerous reports have clearly demonstrated that the synthesis of (rac)-zeaxanthin and its three stereoisomers can be readily accomplished from the Wittig reaction of the racemic or optically active C15-Wittig salt (12 and/or 13) with C10-dialdehyde 6 by a C15+C10+C15 coupling strategy. Furthermore, in the synthetic strategies developed by Loeber et al. [J. Chem. Soc (C), 1971, 404-408] as well as Rüttimann and Mayer (Helv. Chim. Acta, 1980, 63:1456-62), 3-hydroxy-β-ionone has been shown to serve as the key starting material for the total synthesis of zeaxanthin. However, the synthesis of optically active (3R)-3-hydroxy-β-ionone and its (3S)-isomer by a relatively straightforward process is lacking and the development of such a process can considerably simplify the total synthesis of zeaxanthin, β-cryptoxanthin, and their stereoisomers. Therefore, the present invention was developed to provide a more practical route to 8 and 9 by employing a divergent synthetic strategy that could be applied to the synthesis of Wittig salts 12 and 13. These Wittig salts have been utilized in the synthesis of (3R,3′R)-zeaxanthin, (3S,3′S)-zeaxanthin, (3R,3′S;meso)-zeaxanthin, (3R)-β-cryptoxanthin, and (3S)-β-cryptoxanthin.